3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists

Abstract

Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R 1 , R 3 , R 4 and R 5 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).

What is claimed is: 
     
       1. A chemical entity, which is a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is —H; halo; C 1 -C 6  alkyl optionally substituted with 1 to 6 fluoro; C 3 -C 6  cycloalkyl;
 C 1 -C 4  alkoxy optionally substituted with 1 to 6 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SR 7 ; 
 —S(O) 2 R 6 ; or —CO 2 R 7 ; 
 
         Y is C(R 2 ) or N; 
         Z is C(H) or N; 
         R 1  is —H, halo, C 1 -C 4  alkyl optionally substituted with 1 to 3 fluoro; C 3 -C 6  cycloalkyl;
 C 1 -C 4  alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —CO 2 R 7 ; or —C(O)N(R 7 )(R 8 ); 
 
         R 2  is —H; halo; C 1 -C 4  alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; or C 1 -C 4  alkoxy optionally substituted with 1 to 3 fluoro; 
         R 3  is —H, —F, —Cl, —CH 3 , —CF 3  or —OCH 3 ; 
         R 4  is —H, —F; —Cl; C 1 -C 3  alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl; 
         R 5  is —H or —CH 3 ; 
         each instance of R 6  independently is C 1 -C 4  alkyl optionally substituted with 1 to 3 fluoro; 
         each instance of R 7  independently is C 1 -C 4  alkyl; and 
         each instance of R 8  independently is —H or C 1 -C 4  alkyl. 
       
     
     
       2. The chemical entity of  claim 1 , wherein:
 X is —H; —F; —Cl; C 1 -C 4  alkyl; C 1 -C 3  alkyl substituted with 1 to 6 fluoro; cyclopropyl; C 1 -C 4  alkoxy; C 1 -C 2  alkoxy substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SR 7 ; or —S(O) 2 R 6 ; 
 Y is C(R 2 ) or N; 
 Z is C(H) or N; 
 R 1  is —H; —F; —Cl; C 1 -C 4  alkyl; C 1 -C 2  alkyl substituted with 1 to 3 fluoro; cyclopropyl; C 1 -C 4  alkoxy; C 1 -C 2  alkoxy substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —CO 2 R 7 ; or —C(O)N(R 7 )(R 8 ); 
 R 2  is —H; —F; —Cl; C 1 -C 4  alkyl; C 1 -C 2  alkyl substituted with 1 to 3 fluoro; cyclopropyl; C 1 -C 4  alkoxy; C 1 -C 2  alkoxy substituted with 1 to 3 fluoro; 
 R 3  is —H, —F, —Cl, —CH 3 , —CF 3  or —OCH 3 ; 
 R 4  is —H, —F, —Cl, —CH 3 , —CF 3 , or cyclopropyl; 
 R 5  is —H or —CH 3 ; 
 each instance of R 6  independently is C 1 -C 2  alkyl optionally substituted with 1 to 3 fluoro; 
 each instance of R 7  independently is C 1 -C 2  alkyl; and 
 each instance of R 8  independently is —H or C 1 -C 2  alkyl. 
 
     
     
       3. The chemical entity of  claim 1 , wherein:
 X is —H; —F; —Cl; C 1 -C 2  alkyl optionally substituted with 1 to 3 fluoro; or C 1 -C 2  alkoxy optionally substituted with 1 to 3 fluoro; 
 Y is C(R 2 ) or N; 
 Z is C(H) or N; 
 R 1  is —H, halo or —CH 3 ; 
 R 2  is —H, —F, —Cl or —CH 3 ; 
 R 3  is —H, —F, —Cl, —CH 3  or —CF 3 ; 
 R 4  is —H, —F, —CH 3  or —CF 3 ; and 
 R 5  is —H or —CH 3 . 
 
     
     
       4. The chemical entity of  claim 1 , wherein:
 X is —H, —F, —Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCHF 2  or —OCF 3 ; 
 Y is C(R 2 ) or N; 
 Z is C(H) or N; 
 R 1  is —H or —F; 
 R 2  is —H; 
 R 3  is —H, —F or —CF 3 ; 
 R 4  is —H or —CH 3 ; and 
 R 5  is —H or —CH 3 . 
 
     
     
       5. The chemical entity of  claim 1  of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
       6. The chemical entity of  claim 5 , wherein:
 X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 F, —CF 2 CF 3 , —CH(CF 3 ) 2 , —CH 2 CF 2 CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3  or —SO 2 CF 3 ; 
 R 1  is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 ,
 —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2  or —C(O)NH(CH 3 ); 
 
 R 3  is —H, —F, —Cl, —CH 3 , —CF 3  or —OCH 3 ; 
 R 4  is —H, —F; —Cl; C 1 -C 3  alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl; and 
 R 5  is —H or —CH 3 . 
 
     
     
       7. The chemical entity of  claim 5 , wherein:
 X is —H, —F, —Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCHF 2  or —OCF 3 ; 
 R 1  is —H or —F; 
 R 3  is —H, —F or —CF 3 ; 
 R 4  is —H or —CH 3 ; and 
 R 5  is —H or —CH 3 . 
 
     
     
       8. The chemical entity of  claim 5  of formula (IIa): 
       
         
           
           
               
               
           
         
       
     
     
       9. The chemical entity of  claim 1  of formula (III): 
       
         
           
           
               
               
           
         
       
     
     
       10. The chemical entity of  claim 9 , wherein:
 X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH(CF 3 ) 2 , —CH 2 CF 2 CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3  or —SO 2 CF 3 ; 
 R 1  is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2  or —C(O)NH(CH 3 ); 
 R 3  is —H, —F, —Cl, —CH 3 , —CF 3  or —OCH 3 ; 
 R 4  is —H, —F; —Cl; C 1 -C 3  alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl; and 
 R 5  is —H or —CH 3 . 
 
     
     
       11. The chemical entity of  claim 9 , wherein:
 X is —H, —F, —Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCHF 2  or —OCF 3 ; 
 R 1  is —H or —F; 
 R 3  is —H, —F or —CF 3 ; 
 R 4  is —H or —CH 3 ; and 
 R 5  is —H or —CH 3 . 
 
     
     
       12. The chemical entity of  claim 9  of formula (Ma): 
       
         
           
           
               
               
           
         
       
     
     
       13. The chemical entity of  claim 1  of formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
       14. The chemical entity of  claim 1  of formula (V): 
       
         
           
           
               
               
           
         
       
     
     
       15. A pharmaceutical composition comprising the chemical entity  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       16. The pharmaceutical composition of  claim 15 , which is suitable for oral administration. 
     
     
       17. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of  claim 1 . 
     
     
       18. The method of  claim 17 , wherein the disease or disorder is depression, pain, Parkinson's disease, Huntington's disease, Alzheimer's disease, cerebral ischaemia, traumatic brain injury, epilepsy or migraine. 
     
     
       19. The method of  claim 18 , wherein the disease or disorder is depression.